title: Indolizidine (-)-235B' and related structural analogs: discovery of nicotinic receptor antagonists that inhibit nicotine-evoked [3H]dopamine release.
abstract: Although several therapeutic agents are available to aid in tobacco smoking cessation, relapse rates continue to be high, warranting the development of alternative pharmacotherapies. Nicotine-evoked dopamine release from its presynaptic terminals in the central nervous system leads to reward which maintains continued tobacco use. The ability of indolizidine (-)-235B' and a sub-library of structurally related analogs to inhibit nicotine-evoked [(3)H]dopamine release from rat striatal slices was determined in the current study. Indolizidine (-)-235B' inhibited nicotine-evoked [(3)H]dopamine release in a concentration-dependent manner (IC(50)=42 nM, I(max)=55%). Compound (-)-237D, the double bond-reduced analog, afforded the greatest inhibitory potency (IC(50)=0.18 nM, I(max)=76%), and was 233-fold more potent than indolizidine (-)-235B'. The des-8-methyl aza-analog of indolizidine (-)-235B', ZZ-272, also inhibited nicotine-evoked [(3)H]dopamine release (IC(50)=413 nM, I(max)=59%). Concomitant exposure to maximally effective concentrations of indolizidine (-)-235B', ZZ-272 or (-)-237D with a maximally effective concentration of α-conotoxin MII, a selective antagonist for α6β2-containing nicotinic receptors, resulted in inhibition of nicotine-evoked [(3)H]dopamine release no greater than that produced by each compound alone. The latter results suggest that indolizidine (-)-235B', (-)-237D, ZZ-272 and α-conotoxin MII inhibit the same α-conotoxin MII-sensitive nicotinic receptor subtypes. Thus, indolizidine (-)-235B' and its analogs act as antagonists of α6β2-nicotinic receptors and constitute a novel structural scaffold for the discovery of pharmacotherapies for smoking cessation.
authors.affiliation: Department of Pharmaceutical Science, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Marharyta
authors.initials: M
authors.lastname: Pivavarchyk
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Smith
authors.forename: Zhenfa
authors.initials: Z
authors.lastname: Zhang
authors.forename: Dejun
authors.initials: D
authors.lastname: Zhou
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.forename: Naoki
authors.initials: N
authors.lastname: Toyooka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsuneki
authors.forename: Toshiyasu
authors.initials: T
authors.lastname: Sasaoka
authors.forename: J Michael
authors.initials: JM
authors.lastname: McIntosh
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks
authors.forename: Linda P
authors.initials: LP
authors.lastname: Dwoskin
mesh_terms: D000818:Animals; D020916:Conotoxins / Q000494:pharmacology; D004298:Dopamine / Q000737:chemistry / Q000378:metabolism*; D055808:Drug Discovery; D004347:Drug Interactions; D066298:In Vitro Techniques; D007212:Indolizines / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D009538:Nicotine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D014316:Tritium / Q000737:chemistry*
chemical_list: C493291:4-(6-heptenyl)-8-methylindolizidine; D020916:Conotoxins; D007212:Indolizines; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; C098872:alpha-conotoxin MII; D014316:Tritium; D009538:Nicotine; D004298:Dopamine